title: An isoform-specific SnoN1-FOXO1 repressor complex controls neuronal morphogenesis and positioning in the mammalian brain.
abstract: Control of neuronal positioning is fundamental to normal brain development. However, the cell-intrinsic mechanisms that govern neuronal positioning remain to be elucidated. Here, we report that the spliced protein products of the transcriptional regulator SnoN, SnoN1 and SnoN2, harbor opposing functions in the coordinate regulation of neuronal branching and positioning. Knockdown of SnoN2 stimulates axon branching in primary neurons and impairs migration of granule neurons in the rat cerebellar cortex in vivo. By contrast, SnoN1 knockdown suppresses SnoN2 knockdown-induced neuronal branching and strikingly triggers excessive migration of granule neurons in the cerebellar cortex. We also find that SnoN1 forms a complex with the transcription factor FOXO1 that represses the X-linked lissencephaly gene encoding doublecortin (DCX). Accordingly, repression of DCX mediates the ability of SnoN1 to regulate branching in primary neurons and granule neuron migration in vivo. These data define an isoform-specific SnoN1-FOXO1 transcriptional complex that orchestrates neuronal branching and positioning in the brain with important implications for the study of developmental disorders of cognition and epilepsy.
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Mai Anh
authors.initials: MA
authors.lastname: Huynh
authors.forename: Yoshiho
authors.initials: Y
authors.lastname: Ikeuchi
authors.forename: Stuart
authors.initials: S
authors.lastname: Netherton
authors.forename: Luis
authors.initials: L
authors.lastname: de la Torre-Ubieta
authors.forename: Rahul
authors.initials: R
authors.lastname: Kanadia
authors.forename: Judith
authors.initials: J
authors.lastname: Stegmüller
authors.forename: Constance
authors.initials: C
authors.lastname: Cepko
authors.forename: Shirin
authors.initials: S
authors.lastname: Bonni
authors.forename: Azad
authors.initials: A
authors.lastname: Bonni
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D048430:Cell Shape / Q000502:physiology*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000502:physiology*; D000089662:Doublecortin Protein; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D047468:Immunoprecipitation; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D051381:Rats; D020318:Rats, Long-Evans; D014157:Transcription Factors / Q000378:metabolism*; D000071161:Forkhead Box Protein O1
chemical_list: D000089662:Doublecortin Protein; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; C000714848:Dcx protein, rat; C511209:Skil_v1 protein, rat; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1